Abstract
BackgroundSelenite is a promising anticancer agent which has been shown to induce apoptosis in malignant mesothelioma cells in a phenotype-dependent manner, where cells of the chemoresistant sarcomatoid phenotype are more sensitive.MethodsIn this paper, we investigate the apoptosis signalling mechanisms in sarcomatoid and epithelioid mesothelioma cells after selenite treatment. Apoptosis was measured with the Annexin-PI assay. The mitochondrial membrane potential, the expression of Bax, Bcl-XL, and the activation of caspase-3 were assayed with flow cytometry and a cytokeratin 18 cleavage assay. Signalling through JNK, p38, p53, and cathepsins B, D, and E was investigated with chemical inhibitors. Furthermore, the expression, nuclear translocation and DNA-binding activity of p53 was investigated using ICC, EMSA and the monitoring of p21 expression as a downstream event. Levels of thioredoxin (Trx) were measured by ELISA.ResultsIn both cell lines, 10 μM selenite caused apoptosis and a marked loss of mitochondrial membrane potential. Bax was up-regulated only in the sarcomatoid cell line, while the epithelioid cell line down-regulated Bcl-XL and showed greater caspase-3 activation. Nuclear translocation of p53 was seen in both cell lines, but very little p21 expression was induced. Chemical inhibition of p53 did not protect the cells from apoptosis. p53 lost its DNA binding ability after selenite treatment and was enriched in an inactive form. Levels of thioredoxin decreased after selenite treatment. Chemical inhibition of MAP kinases and cathepsins showed that p38 and cathepsin B had some mediatory effect while JNK had an anti-apoptotic role.ConclusionWe delineate pathways of apoptosis signalling in response to selenite, showing differences between epithelioid and sarcomatoid mesothelioma cells. These differences may partly explain why sarcomatoid cells are more sensitive to selenite.
Highlights
Selenite is a promising anticancer agent which has been shown to induce apoptosis in malignant mesothelioma cells in a phenotype-dependent manner, where cells of the chemoresistant sarcomatoid phenotype are more sensitive
We have recently shown that selenite induces apoptosis in malignant mesothelioma cells in a dose, time- and phenotype-dependent manner, with a more potent effect on sarcomatoid cells [1,2]
Redox regulation is likely to influence cellular sensitivity to selenite, and we have reported that selenite decreases the activity of thioredoxin reductase (TrxR) [1]
Summary
Selenite is a promising anticancer agent which has been shown to induce apoptosis in malignant mesothelioma cells in a phenotype-dependent manner, where cells of the chemoresistant sarcomatoid phenotype are more sensitive. Selenite is a redox-modulating compound which is increasingly investigated for use as an anticancer agent. We have recently shown that selenite induces apoptosis in malignant mesothelioma cells in a dose-, time- and phenotype-dependent manner, with a more potent effect on sarcomatoid cells [1,2]. Redox regulation is likely to influence cellular sensitivity to selenite, and we have reported that selenite decreases the activity of thioredoxin reductase (TrxR) [1]. Together with thioredoxin (Trx) and NADPH, it forms the thioredoxin system, which is highly active in redox signalling and defence against oxidative stress
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